1. Field of the Invention
The present invention relates to novel bicyclic compounds structurally related to diketopiperazines and methods for their therapeutic use. In particular, this invention relates to the neuroprotective activity of such compounds. More particularly, this invention relates to the use of cyclic Glycyl-2-Allyl Proline (“cyclic G-2AllylP” or “cG-2AllylP”) and pharmaceutical compositions thereof in the treatment of Parkinson's Disease.
2. Related Art
Degeneration and/or death of cells in the nervous system are major factors in many diseases and medical conditions. Such diseases and conditions include traumatic brain and spinal cord injuries, stroke, neural perfusion secondary to cardiac arterial bypass graft surgery (CABG), Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis and other neurodegenerative diseases. It is of interest to prevent or decrease such cell death and degeneration.
Certain compounds are useful as neuroprotective agents. One such compound is insulin-like growth factor 1 (IGF-1) (Scheepens et al, WO00/13650). IGF-1 is a naturally occurring peptide that can decrease the binding of glutamate to the glutamate receptors of neurons (Bourguinon, U.S. Pat. No. 5,804,550). IGF-1 can also decrease neuronal degradation caused by damage and disease. IGF-1 is cleaved by proteolysis in vivo to give des1-3 IGF-1 and the N-terminal tripeptide Gly-Pro-Glu (GPE). GPE and analogues have been found to be neuroprotective (Gluckman et al, U.S. Pat. No. 6,187,906 incorporated herein by reference).
However, such peptides are far from ideal for the treatment of progressive neuronal loss and chronic degeneration especially as they are rapidly metabolised in vivo. There is a need for compounds that provide neuroprotective and neuroregenerative properties and are more metabolically stable especially as regards resistance to proteases.
A derivative of GPE; cyclic Pro-Gly (“cPG”), a diketopiperazine, has been shown to be neuroprotective and neuroregenerative. cPG was found to prevent toxic neural degeneration and cell death and to promote neurite outgrowth in neurons (Guan et al, PCT/US02/36235 incorporated herein by reference). Diketopiperazine analogues of thyrotropin-releasing hormone (TRH) are known to be neuroprotective (Kozikowski et al WO99/40931).
Parkinson's disease is a chronic and progressive motor system disorder. Its symptoms include: tremor, rigidity, bradykinesia, joint and muscle pain due to immobility, poor righting reflexes, dribbling, constipation, postural hypotension or dementia. The cause of the disease is unknown but the symptoms are the consequence of substantial loss of dopaminergic neurons in the pars compacta region of the substantia nigra. In some patients with a history of Parkinson's disease, motor or other symptoms may be episodic, with periods of time that are relatively symptom free, and other periods where symptoms worsen. Thus, there is a need for agents that can be used to reverse adverse symptoms when they occur, and to prevent of decrease the likelihood of appearance of an episode of adverse symptoms.
The main therapy currently used, L-DOPA treatment, is known to cause side-effects such as nausea, vomiting, postural hypotension, confusion or, when the treatment is continued extended periods of time, dyskinesia. Other available therapies including dopamine agonists, anticholinergic drugs, catechol-0-methyl-transferase inhibitors or amantadine, are less effective and also associated with a number of often serious side-effects. There is clearly a need for a therapy, which could help Parkinson's disease sufferers and reduce the number or severity of side-effects in comparison with the available treatment methods.